Myeloid Cell-Derived Arginase in Cancer Immune Response

Abstract

Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.

Keywords: T lymphocyte; T-cell metabolism; arginase; arginine; immunosuppression; immunotherapy; tumor immunology.

Figure 1

Scheme for arginine metabolism. In mammalian cells, L-Arginine is a substrate for four enzymes: ARG, NOS, ADC, AGAT. L-Arginine downstream metabolites are components of multiple metabolic pathways and are necessary for cells proliferation and collagen synthesis. ADC, arginine decarboxylase; AGAT, arginine:glycine amidinotransferase; AGMase, agmatinase; ARG, arginase; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; GAMT, guanidinoacetate N-methyltransferase; NOS, nitric oxide synthase; OAT; ornithine aminotransferase; OTC, ornithine transcarbamylase; P5C, pyrroline-5-carboxylic acid. Figure was modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. http://smart.servier.com/.

Figure 2

Cancer cells recruit myeloid cells to tumor microenvironment (TME) and induce their polarization to immunosuppressive phenotype. Myeloid cells, including macrophages, MDSC, dendritic cells, and neutrophils create tumor-promoting, immunosuppressive TME via multiple factors including reactive oxygen species (ROS), cytokines (IL-10, TGF-β), PD-L1, as well as ARG1. Created with BioRender.

Figure 3

L-Arginine-depleting arginases lead to the impaired anti-tumor response. Arginases may act intracellularly (cytoplasmic ARG1 and mitochondrial ARG2) and extracellularly (secreted ARG1) leading to the local depletion of L-arginine in tumor microenvironment (TME). Moreover, ARG1 may have effects in sites distant from the TME, when packed into extracellular vesicles (EVs), transported over long distance and internalized by myeloid cells, for instance, in tumor-draining lymph node. Arginase inhibitors (ARGi) should target both isoforms (ARG1 and ARG2) and easily penetrate the cell membrane to block extracellular and intracellular arginases, as well as arginase in EVs. Created with BioRender.

Figure 4

Several tumor-associated factors promote ARG1 expression in myeloid cells. ARG1 expression is mainly induced by type 2 cytokines (IL-4, IL-13), as well as immunosuppressive cytokines (TGF-β, IL-10). Moreover, it may be promoted by TME factors including hypoxia and acidosis, as well as stress mediators. ARG1 expression is also induced by GM-CSF (136), TLR agonists (137), and cAMP (138). IL-10 and IL-21 increase IL-4-induced ARG1 expression (139, 140). Created with BioRender.

Figure 5

L-Arginine depletion by arginase potently inhibits immune response. Lack of L-arg completely inhibits proliferation of T-cells and leads to the decreased cytokine production. It is caused by downregulation of signal-transducing CD3ζ chain, cell cycle arrest, and affected formation of the immune synapse between T-cells and APC. Created with BioRender.